Abstract: In response to the request for applications DK-05-011, entitled Animal Models of Diabetic Complications Consortium (AMDCC), the Investigators from the current AMDCC Neuropathy Phenotyping Core are proposing to develop 2 new mouse models of diabetic neuropathy (DN) targeting the biochemical pathways of oxidative stress. Our general strategic approach is to accelerate glucose-mediated oxidative injury in neurons in genetic models of type 2 diabetes. While many gene products participate in this process, we will concentrate on targeting 2 enzymes involved in superoxide detoxification: mitochondrial superoxide dismutase 2 (SOD2) and catalase. Our initial approach will concentrate on developing 2 Cre-loxP models on a susceptible genetic background. In parallel, we propose 2 hypothesis-driven specific aims for discovering the basic pathophysiologic mechanisms underlying DN. Aim 1 will test the hypothesis that decreased catalase activity in sensory neurons will make these neurons more susceptible to glucose-mediated injury. Aim 2 will test the hypothesis that animal models with DN have morphological and biochemical markers of increased oxidative stress in the peripheral nervous system. Information gained from this application will lead to new insights into the pathogenesis of DN and allow for the development of more relevant murine models of this disabling complication. Relevance to Public Health: 20 million Americans are diabetic and the incidence is increasing by 5% each year. Although DN is a common and highly morbid condition, there are no treatments for DN outside of control of the diabetic condition itself. Our studies will identify cellular targets for treatment of DN and have the potential to benefit all patients with diabetes.

Institution:

University of Michigan
3003 SOUTH STATE STREET
ANN ARBOR, MI

Fiscal Year:

2006

Department:

NEUROLOGY

Project Start:

9/30/2006

Project End:

8/31/2011

ICD:

NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES

SubContract(s)

A Centralized Data Mining and Analysis Portal for Diabetic Neuropathy Research

Diabetic neuropathy (DN) is the most common complication of diabetes with significant morbidity, mortality and cost. 60% - 70% of diabetic patients have neuropathy often resulting in poor quality of life. Better understanding of the molecular mechanism of development and progression of DN is crucial for designing mechanism based therapies. Genome-wide molecular studies in animal models are integral to understanding human disease pathogenesis. Diabetic Complications Consortium (DCC) has extensively characterized mouse models of human DN. Integrating high-throughput gene expression data in human DN with those in the animal models is critical in delineating species-specific as well as shared mechanisms between human and mouse. Our group has developed a database system that integrates transcriptomics data from our studies in mouse models and human DN. Goal of this proposal is to extend the existing system to form a centralized repository for publicly available transcriptomics data sets of DN and to provide a data-mining and data-analysis portal to the diabetes complications research community. Specific aims of the project are: Aim 1. Identify and annotate human and mouse DN gene expression data sets in the DCC data repository, National Center for Biotechnology Information (NCBI) Gene Expression Omnibus and European Bioinformatics Institute (EBI) ArrayExpress; process data using our established data processing pipeline to achieve consistency. Aim 2. Extend the existing database to efficiently store large transcriptomics data sets and upload processed data into the database; develop and implement data mining and data analysis tools with a user friendly web-based interface. Making this centralized data repository and analysis portal available to the research community at large will aid investigators in generating hypotheses and designing future experiments. Comparing gene regulation in the well characterized DCC murine models and human DN will facilitate selection of models that best recapitulate human disease mechanism for further exploration.

Identifying Alterations in Mitochondrial Dynamics Associate

Diabetes is a growing epidemic, affecting more than 387 million individuals worldwide. Up to 60% of diabetic patients have diabetic neuropathy (DN), a debilitating microvascular complication that results in the progressive loss of sensory nerve function in the extremities. Despite the deleterious impact of DN, therapies for the disease are limited to symptomatic relief. To develop effective treatments that specifically target DN, a mechanistic understanding of molecular pathways that result in neurological dysfunction associated with diabetes is needed. Recent evidence suggests that dyslipidemia, rather than hyperglycemia, is the clinical parameter that correlates with the progression of DN. Since metabolic pathways converge on the mitochondria (Mt), these organelles play a central role in maintaining neuronal cellular function and energy homeostasis through mitochondrial (Mtl) trafficking mechanisms and endoplasmic reticulum (ER)-mediated calcium signaling pathways. However, metabolic overload associated with diabetes may result in aberrant calcium dynamics in the primary sensory neurons of the nervous system, the dorsal root ganglia (DRG), resulting in diminished Mtl trafficking and cell death induced by ER-Mt contact sites. We hypothesize that hyperlipidemia increases the level of ER-Mt contact sites in DRG neurons, creating a localized calcium flux which triggers Mtl apoptosis and halts Mtl trafficking. We will test this hypothesis by 1) evaluating the role of ER-Mt interactions in Mtl dysfunction and neuronal cell death in the DRG and sural nerve of a high fat (HF)-fed mouse model, and 2) identifying changes in calcium dynamics that impair Mtl trafficking in hyperlipidemic DRG neurons. These studies will provide important insight into the role of Mtl dynamics in DN and thereby support our long-term goal of identifying therapeutic targets that specifically improve Mtl function and restore nerve function to patients with DN.

The DiaComp Steering Committee is the governing body of the consortium. The principle function of this committee is to guide the scientific direction of the consortium. This is accomplished by creating various subcommittees necessary to advance the scientific goals and providing guidance to the broader complications research community. Policies for the consortium are developed through consultation with the External Evaluation Committee